2. Academic Validation
  3. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

  • Nat Commun. 2019 Jul 12;10(1):3094. doi: 10.1038/s41467-019-10910-w.
Vincenzo Salpietro 1 2 3,  Christine L Dixon 4,  Hui Guo 5 6,  Oscar D Bello 4,  Jana Vandrovcova 1,  Stephanie Efthymiou 1 4,  Reza Maroofian 1,  Gali Heimer 7,  Lydie Burglen 8,  Stephanie Valence 9,  Erin Torti 10,  Moritz Hacke 11,  Julia Rankin 12,  Huma Tariq 1,  Estelle Colin 13 14,  Vincent Procaccio 13 14,  Pasquale Striano 2 3,  Kshitij Mankad 15,  Andreas Lieb 4,  Sharon Chen 16,  Laura Pisani 16,  Conceicao Bettencourt 17,  Roope Männikkö 1,  Andreea Manole 1,  Alfredo Brusco 18,  Enrico Grosso 18,  Giovanni Battista Ferrero 19,  Judith Armstrong-Moron 20,  Sophie Gueden 21,  Omer Bar-Yosef 7,  Michal Tzadok 7,  Kristin G Monaghan 10,  Teresa Santiago-Sim 10,  Richard E Person 10,  Megan T Cho 10,  Rebecca Willaert 10,  Yongjin Yoo 22,  Jong-Hee Chae 23,  Yingting Quan 6,  Huidan Wu 6,  Tianyun Wang 5 6,  Raphael A Bernier 24,  Kun Xia 6,  Alyssa Blesson 25,  Mahim Jain 25,  Mohammad M Motazacker 26,  Bregje Jaeger 27,  Amy L Schneider 28,  Katja Boysen 28,  Alison M Muir 29,  Candace T Myers 30,  Ralitza H Gavrilova 31,  Lauren Gunderson 31,  Laura Schultz-Rogers 31,  Eric W Klee 31,  David Dyment 32,  Matthew Osmond 32 33 34,  Mara Parellada 35,  Cloe Llorente 36,  Javier Gonzalez-Peñas 37,  Angel Carracedo 38 39,  Arie Van Haeringen 40,  Claudia Ruivenkamp 40,  Caroline Nava 41,  Delphine Heron 41,  Rosaria Nardello 42,  Michele Iacomino 43,  Carlo Minetti 2 3,  Aldo Skabar 44,  Antonella Fabretto 44,  SYNAPS Study Group,  Miquel Raspall-Chaure 45,  Michael Chez 46,  Anne Tsai 47,  Emily Fassi 48,  Marwan Shinawi 48,  John N Constantino 49,  Rita De Zorzi 50,  Sara Fortuna 50,  Fernando Kok 51 52,  Boris Keren 41,  Dominique Bonneau 13 14,  Murim Choi 22,  Bruria Benzeev 7,  Federico Zara 43,  Heather C Mefford 29,  Ingrid E Scheffer 28,  Jill Clayton-Smith 53 54,  Alfons Macaya 45,  James E Rothman 4 55,  Evan E Eichler 5 56,  Dimitri M Kullmann 57,  Henry Houlden 58
Affiliations

Affiliations

  • 1 Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
  • 2 Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "Giannina Gaslini", 16147, Genoa, Italy.
  • 3 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy.
  • 4 Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
  • 5 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, 98195, USA.
  • 6 Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China.
  • 7 Pediatric Neurology Unit, Safra Children's Hospital, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 526121, Ramat Gan, Israel.
  • 8 Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique et Embryologie Médicale, APHP, Hôpital Trousseau, 75012, Paris, France.
  • 9 Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Service de Neurologie Pédiatrique, APHP, Hôpital Trousseau, 75012, Paris, France.
  • 10 GeneDx, Gaithersburg, MD, 20877, USA.
  • 11 Biochemistry Center, Heidelberg University, D-69120, Heidelberg, Germany.
  • 12 Royal Devon and Exeter NHS Foundation Trust, Exeter, EX1 2ED, UK.
  • 13 Department of Biochemistry and Genetics, University Hospital, 49933, Angers, France.
  • 14 MitoLab, UMR CNRS 6015-INSERM U1083, MitoVasc Institute, Angers University, 49100, Angers, France.
  • 15 Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
  • 16 Division of Medical Genetics, Northwell Health/Hofstra University SOM, New York, 11020, USA.
  • 17 Department of Clinical and Movement Neurosciences and Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, UK.
  • 18 Department of Medical Sciences, Medical Genetics Unit, University of Torino, 10126, Torino, Italy.
  • 19 Department of Public Health and Pediatrics, University of Torino, 10126, Torino, Italy.
  • 20 Unit of Medical and Molecular Genetics, University Hospital Sant Joan de Deu Barcelona, 08950, Barcelona, Spain.
  • 21 Unit of Neuropediatrics, University Hospital, Angers Cedex, 49933, France.
  • 22 Department of Biomedical Sciences, Seoul National University, Seoul, 03080, South Korea.
  • 23 Department of Pediatrics, Seoul National University, Seoul, 03080, South Korea.
  • 24 Department of Psychiatry, University of Washington, Seattle, WA, 98195, USA.
  • 25 Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, Maryland, 21211, USA.
  • 26 Department of Clinical Genetics, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, Netherlands.
  • 27 Department of Pediatric Neurology, Amsterdam UMC, 1105, Amsterdam, Netherlands.
  • 28 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, 3084, Australia.
  • 29 Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA.
  • 30 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, 98195, USA.
  • 31 Department of Clinical Genomics, Mayo Clinic, Rochester, 55902, MN, USA.
  • 32 Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, K1H 8L1, Canada.
  • 33 Department of Human Genetics, McGill University Health Centre, Montréal, QC, H4A 3J1, Canada.
  • 34 Genome Québec Innovation Center, Montréal, QC, H3A 0G1, Canada.
  • 35 Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, 28007, Madrid, Spain.
  • 36 Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Maranon, Universidad Complutense, CIBERSAM, 28007, Madrid, Spain.
  • 37 Hospital Gregorio Maranon, IiSGM, School of Medicine, Calle Dr Esquerdo, 46, 28007, Madrid, Spain.
  • 38 Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CIMUS, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain.
  • 39 Fundación Pública Galega de Medicina Xenómica- IDIS- Servicio Galego de Saúde (SERGAS), 15706, 15782, Santiago de Compostela, Spain.
  • 40 Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA, Leiden, Netherlands.
  • 41 Department of Genetics, Assistance Publique - Hôpitaux de Paris, University Hôpital Pitié-Salpêtrière, 75013, Paris, France.
  • 42 Department of Health Promotion,Mother and Child Care, Internal Medicine and Medical Specialities "G. D'Alessandro", University of Palermo, 90133, Palermo, Italy.
  • 43 Laboratory of Neurogenetics and Neuroscience, IRCCS Istituto "Giannina Gaslini", 16147, Genova, Italy.
  • 44 Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", University of Trieste, 34134, Trieste, Italy.
  • 45 Department of Pediatric Neurology, University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
  • 46 Neuroscience Medical Group, 1625 Stockton Boulevard, Suite 104, Sacramento, CA, 95816, USA.
  • 47 Department of Genetics and Inherited Metabolic diseases, Children's Hospital Colorado, Aurora, CO, 80045, USA.
  • 48 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 49 William Greenleaf Eliot Division of Child & Adolescent Psychiatry, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 50 Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34134, Trieste, Italy.
  • 51 Neurogenetics Unit, Department of Neurology, University of Sao Paulo, Sao Paulo, 01308-000, Brazil.
  • 52 Mendelics Genomic Analysis, Sao Paulo, SP, 04013-000, Brazil.
  • 53 Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Lancashire, M13 9WL, UK.
  • 54 Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, M13 9WL, UK.
  • 55 Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06520, USA.
  • 56 Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, USA.
  • 57 Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK. [email protected].
  • 58 Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK. [email protected].
PMID: 31300657 DOI: 10.1038/s41467-019-10910-w
Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

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